tbuckley/cabot-search huggingface dataset:
Falling employment and worsening health in the UK: connected or distinct trends?
Authors: Jonathan Cribb
Journal: BMJ (2023)

Two concerning economic and social trends in the UK emerging from the covid-19 pandemic are the fall in employment of people aged 50 and over and the increase in sickness levels in the population.The drop in employment has not been caused by rising unemployment (when people are generally searching for work), but rather by rising "economic inactivity" (when they generally are not). 1 These declines have not occurred in most industrialised nations with a notable exception of the US. 2 3 A natural conclusion might be that the two trends are related.But a closer look at the data implies that-in 2020-21 at least-these issues have been quite distinct.
Tumor Therapy Strategies Based on Microenvironment‐Specific Responsive Nanomaterials
Authors: Zhaocong Zhang, Chengwen Ding, Tiedong Sun, Lei Wang, Chunxia Chen
Journal: Advanced Healthcare Materials (2023)

Abstract The tumor microenvironment (TME) is a complex and variable region characterized by hypoxia, low pH, high redox status, overexpression of enzymes, and high‐adenosine triphosphate concentrations. In recent years, with the continuous in‐depth study of nanomaterials, more and more TME‐specific response nanomaterials are used for tumor treatment. However, the complexity of the TME causes different types of responses with various strategies and mechanisms of action. Aiming to systematically demonstrate the recent advances in research on TME‐responsive nanomaterials, this work summarizes the characteristics of TME and outlines the strategies of different TME responses. Representative reaction types are illustrated and their merits and demerits are analyzed. Finally, forward‐looking views on TME‐response strategies for nanomaterials are presented. It is envisaged that such emerging strategies for the treatment of cancer are expected to exhibit dramatic trans‐clinical capabilities, demonstrating the extensive potential for the diagnosis and therapy of cancer.
When I use a word . . . . Defining with finesse
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

The word for a definition in both Latin and Greek is a word meaning or derived from a word meaning a boundary. In Greek it is ὅρισμός (horismos) from ὅρος (horos), a boundary. The horizon is a kind of boundary, and a definition is limited by its horizon, the place beyond which no more meaning should be included. In Latin the word for a definition is finis, which also means a boundary. Five features characterise a good definition: it should describe all the essential attributes of the thing being defined, no more no less; it should avoid circularity, such as defining a medication error as an error in medication; it should be neither too wide nor too narrow; it should not use obscure terms that may themselves need definition; and it should be couched in positive terms, saying what something is, not what it is not. All of these apply as much to definitions of medical words as to any other kinds.
Letter to the Editor: Hepatic interferon regulatory factor 8 expression suppresses HCC progression and enhances the response to anti–programmed cell death protein-1 therapy
Authors: Wei Zhang, Ming-kao Wang, Dan Yao, Hai-jian Zhao, Xiao-yu Zhang
Journal: Hepatology (2023)

Zhang, Wei; Wang, Ming-kao; Yao, Dan; Zhao, Hai-jian; Zhang, Xiao-yu Author Information
In defence of the National Health Service
Authors: Cam Donaldson
Journal: BMJ (2023)

The NHS is under huge pressure, with new reports or news stories appearing constantly about the crisis it faces. 1In July 2022, the BBC reported a 39 per cent increase in self-funded care, with patients paying the full cost of some procedures, such as knee and hip replacements.Deregulation and charges are openly promoted. 2 3In the summer, it was reported that Rishi Sunak, the UK prime minister, was advocating financial penalties for missed GP appointments.More recently, it was reported that he is registered with a private GP.
Is this really thalassemia?
Authors: Benoit Thomas, Sorin Visanica, Sophie Poussing, Delphine Gérard, Julien Perrin
Journal: American Journal of Hematology (2023)

As these studies did not indicate a diagnosis of thalassemia, a bone marrow aspiration was performed, revealing a marked erythroid hyperplasia (64%) with dyserythropoiesis, defective hemoglobinization, hypochromia and marked basophilic stippling (Image C–E). Perls staining showed 85% ring sideroblasts (Image F). Serum copper and vitamin B6 levels as well as the karyotype were normal. A congenital sideroblastic anemia gene panel (ALAS2, SLC25A38, GLRX5, ABCB7, SLC19A2, TRNT1, PUS1, YARS2, HSPA9, LARS2, NDUFB11, SFXN4) revealed the presence of a novel hemizygous variation p.Arg411Ser (c.1231C>A) in 5-aminolevulinic acid synthase (ALAS2), supporting the diagnosis of X-linked sideroblastic anemia (XLSA). Congenital sideroblastic anemias are a heterogenous group of inherited disorders, affecting heme synthesis, iron–sulfur cluster biogenesis, or the synthesis of other mitochondrial proteins.1, 2 ALAS2 is the first enzyme in heme synthesis and XLSA is the most common form. Although inherited, it often becomes more severe with age and is frequently associated with progressive iron overload and splenomegaly. Abnormalities on the blood smear share some features with thalassemia including anisopoikilocytosis and basophilic stippling, but there are characteristically few target cells and often a dimorphic population of hypochromic, microcytic cells coexisting with nearly normal erythrocytes. Although the ALAS2 variant, p.Arg411Ser, observed in this patient has not previously been reported, other mutations, p.Arg411His/Cys are among the most common mutations observed in affected males.3, 4 Pyridoxal phosphate is the co-enzyme of ALAS2, and in approximately two-thirds of the cases, anemia responds to vitamin B6. Indeed, in the present case, vitamin B6 (250 mg, 3 times a day) and folate (5 mg, twice a day, the first 3 months only) resulted in an increase in the HGB to ~10 g/dL. Meanwhile, his iron overload was improved (around 1500 μg/L) by oral deferasirox (720 mg/day).Thus, while thalassemia syndromes and hemoglobinopathies are the most common types of inherited microcytic anemia, other forms, particularly those that are amenable to relatively simple treatments should be considered in the absence of characteristic laboratory and/or genetic findings. The authors declare no conflicts of interest.
Review of Natural Language Processing in Pharmacology
Authors: Dimitar Trajanov, Vangel Trajkovski, Makedonka Dimitrieva, Jovana Dobreva, Milos Jovanovik, Matej Klemen, Aleš Žagar, Marko Robnik-Šikonja
Journal: Pharmacological Reviews (2023)

Natural language processing (NLP) is an area of artificial intelligence that applies information technologies to process the human language, understand it to a certain degree, and use it in various applications. This area has rapidly developed in the last few years and now employs modern variants of deep neural networks to extract relevant patterns from large text corpora. The main objective of this work is to survey the recent use of NLP in the field of pharmacology. As our work shows, NLP is a highly relevant information extraction and processing approach for pharmacology. It has been used extensively, from intelligent searches through thousands of medical documents to finding traces of adversarial drug interactions in social media. We split our coverage into five categories to survey modern NLP methodology, commonly addressed tasks, relevant textual data, knowledge bases, and useful programming libraries. We split each of the five categories into appropriate subcategories, describe their main properties and ideas, and summarize them in a tabular form. The resulting survey presents a comprehensive overview of the area, useful to practitioners and interested observers. <b>Significance Statement</b> The main objective of this work is to survey the recent use of NLP in the field of pharmacology, in order to provide a comprehensive overview of the current state in the area after the rapid developments which occurred in the last few years. We believe the resulting survey to be useful to practitioners and interested observers in the domain.
SOX2 dosage sustains tumor-promoting inflammation to drive disease aggressiveness by modulating the FOSL2/IL6 axis
Authors: Abdel Jelil Njouendou, Tibor Szarvas, Arnol Auvaker Zebaze Tiofack, Rovaldo Nguims Kenfack, Pamela Derliche Tonouo, Sidonie Noa Ananga, Esther H. M. Dina Bell, Gustave Simo, Jörg D. Hoheisel, Jens T. Siveke, Smiths S. Lueong
Journal: Molecular Cancer (2023)

Abstract Background Inflammation is undoubtedly a hallmark of cancer development. Its maintenance within tumors and the consequences on disease aggressiveness are insufficiently understood. Methods Data of 27 tumor entities (about 5000 samples) were downloaded from the TCGA and GEO databases. Multi-omic analyses were performed on these and in-house data to investigate molecular determinants of tumor aggressiveness. Using molecular loss-of-function data, the mechanistic underpinnings of inflammation-induced tumor aggressiveness were addressed. Patient specimens and in vivo disease models were subsequently used to validate findings. Results There was significant association between somatic copy number alterations (sCNAs) and tumor aggressiveness. SOX2 amplification was the most important feature among novel and known aggressiveness-associated alterations. Mechanistically, SOX2 regulates a group of genes, in particular the AP1 transcription factor FOSL2 , to sustain pro-inflammatory signaling pathways, such as IL6-JAK-STAT3 , TNFA and IL17 . FOSL2 was found overexpressed in tumor sections of specifically aggressive cancers. In consequence, prolonged inflammation induces immunosuppression and activates cytidine deamination and thus DNA damage as evidenced by related mutational signatures in aggressive tumors. The DNA damage affects tumor suppressor genes such as TP53, which is the most mutated gene in aggressive tumors compared to less aggressive ones (38% vs 14%), thereby releasing cell cycle control. These results were confirmed by analyzing tissues from various tumor types and in vivo studies. Conclusion Our data demonstrate the implication of SOX2 in promoting DNA damage and genome instability by sustaining inflammation via FOSL2/IL6, resulting in tumor aggressiveness.
Quantitative PET tracking of intra-articularly administered 89Zr-peptide-decorated nanoemulsions
Authors: Sandra Díez-Villares, Lara García-Varela, Soraya Groba-de Antas, José Ramón Caeiro, Paula Carpintero-Fernandez, María D. Mayán, Pablo Aguiar, María de la Fuente
Journal: Journal of Controlled Release (2023)
Author Correction: T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control
Authors: Maria M. Steele, Abhinav Jaiswal, Ines Delclaux, Ian D. Dryg, Dhaarini Murugan, Julia Femel, Sunny Son, Haley du Bois, Cameron Hill, Sancy A. Leachman, Young H. Chang, Lisa M. Coussens, Niroshana Anandasabapathy, Amanda W. Lund
Journal: Nature Immunology (2023)
Exosome-derived circCCAR1 promotes CD8 + T-cell dysfunction and anti-PD1 resistance in hepatocellular carcinoma
Authors: Zongqiang Hu, Gang Chen, Yingpeng Zhao, Hongqiang Gao, Laibang Li, Yanfeng Yin, Jie Jiang, Li Wang, Yuanyi Mang, Yang Gao, Shengning Zhang, Jianghua Ran, Li Li
Journal: Molecular Cancer (2023)

Abstract Background Circular RNAs (circRNAs) can be encapsulated into exosomes to participate in intercellular communication, affecting the malignant progression of a variety of tumors. Dysfunction of CD8 + T cells is the main factor in immune escape from hepatocellular carcinoma (HCC). Nevertheless, the effect of exosome-derived circRNAs on CD8 + T-cell dysfunction needs further exploration. Methods The effect of circCCAR1 on the tumorigenesis and metastasis of HCC was assessed by in vitro and in vivo functional experiments. The function of circCCAR1 in CD8 + T-cell dysfunction was measured by enzyme-linked immunosorbent assay (ELISA), western blotting and flow cytometry. Chromatin immunoprecipitation, biotinylated RNA pull-down, RNA immunoprecipitation, and MS2 pull-down assays were used to the exploration of mechanism. A mouse model with reconstituted human immune system components (huNSG mice) was constructed to explore the role of exosomal circCCAR1 in the resistance to anti-PD1 therapy in HCC. Results Increased circCCAR1 levels existed in tumor tissues and exosomes in the plasma of HCC patients, in the culture supernatant and HCC cells. CircCCAR1 accelerated the growth and metastasis of HCC in vitro and in vivo. E1A binding protein p300 (EP300) and eukaryotic translation initiation factor 4A3 (EIF4A3) promoted the biogenesis of circCCAR1, and Wilms tumor 1-associated protein (WTAP)-mediated m6A modification enhanced circCCAR1 stability by binding insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3). CircCCAR1 acted as a sponge for miR-127-5p to upregulate its target WTAP and a feedback loop comprising circCCAR1/miR-127-5p/WTAP axis was formed. CircCCAR1 is secreted by HCC cells in a heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1)-dependent manner. Exosomal circCCAR1 was taken in by CD8 + T cells and caused dysfunction of CD8 + T cells by stabilizing the PD-1 protein. CircCCAR1 promoted resistance to anti-PD1 immunotherapy. Furthermore, increased cell division cycle and apoptosis regulator 1 (CCAR1) induced by EP300 promoted the binding of CCAR1 and β-catenin protein, which further enhanced the transcription of PD-L1. Conclusions The circCCAR1/miR-127-5p/WTAP feedback loop enhances the growth and metastasis of HCC. Exosomal circCCAR1 released by HCC cells contributes to immunosuppression by facilitating CD8 + T-cell dysfunction in HCC. CircCCAR1 induces resistance to anti-PD1 immunotherapy, providing a potential therapeutic strategy for HCC patients.
Generalizable and robust deep learning algorithm for atrial fibrillation diagnosis across geography, ages and sexes
Authors: Shany Biton, Mohsin Aldhafeeri, Erez Marcusohn, Kenta Tsutsui, Tom Szwagier, Adi Elias, Julien Oster, Jean Marc Sellal, Mahmoud Suleiman, Joachim A. Behar
Journal: npj Digital Medicine (2023)

To drive health innovation that meets the needs of all and democratize healthcare, there is a need to assess the generalization performance of deep learning (DL) algorithms across various distribution shifts to ensure that these algorithms are robust. This retrospective study is, to the best of our knowledge, an original attempt to develop and assess the generalization performance of a DL model for AF events detection from long term beat-to-beat intervals across geography, ages and sexes. The new recurrent DL model, denoted ArNet2, is developed on a large retrospective dataset of 2,147 patients totaling 51,386 h obtained from continuous electrocardiogram (ECG). The model's generalization is evaluated on manually annotated test sets from four centers (USA, Israel, Japan and China) totaling 402 patients. The model is further validated on a retrospective dataset of 1,825 consecutives Holter recordings from Israel. The model outperforms benchmark state-of-the-art models and generalized well across geography, ages and sexes. For the task of event detection ArNet2 performance was higher for female than male, higher for young adults (less than 61 years old) than other age groups and across geography. Finally, ArNet2 shows better performance for the test sets from the USA and China. The main finding explaining these variations is an impairment in performance in groups with a higher prevalence of atrial flutter (AFL). Our findings on the relative performance of ArNet2 across groups may have clinical implications on the choice of the preferred AF examination method to use relative to the group of interest.
Publisher Correction: Glucagon receptor antagonist volagidemab in type 1 diabetes: a 12-week, randomized, double-blind, phase 2 trial
Authors: Jeremy Pettus, Schafer C. Boeder, Mark P. Christiansen, Douglas S. Denham, Timothy S. Bailey, Halis K. Akturk, Leslie J. Klaff, Julio Rosenstock, Mickie H. M. Cheng, Bruce W. Bode, Edgar D. Bautista, Ren Xu, Hai Yan, Dung Thai, Satish K. Garg, Samuel Klein
Journal: Nature Medicine (2023)
Letter to the Editor: The associations between hepatic steatosis and incident cardiovascular disease and all-cause mortality
Authors: Zheyu Li, Liting Zhang, Junfeng Li
Journal: Hepatology (2023)

To the editor, We read with great interest the recent article in Hepatology by Ahmed et al.1 Impressively, Ahmed and colleagues not only adjusted for cardiovascular disease (CVD) risk factors in baseline but also adjusted for changes in CVD risk factors over time. The associations between hepatic steatosis and incident CVD and all-cause mortality were attenuated when accounting for a change in CVD risk factors over time. However, we have different views on the appropriateness of the adjustment for changes in CVD risk factors over time. On the one hand, CVD risk factors, especially type 2 diabetes,2 are associated with the development of NAFLD, so the time-varying covariates of CVD risk factors may reflect changes in the severity of NAFLD. On the other hand, time-varying covariates of CVD risk factors may be associated with the corresponding treatments received by the patients, and these treatments may have additional effects on hepatic steatosis. For example, statins have been shown to reduce the risk of NAFLD occurrence and fibrosis in a large population study.3 Similarly, a meta-analysis has suggested that thiazolidinedione and glucagon-like peptide-1 receptor agonists were effective in attenuating hepatic fat content.4 As a result, adjusting for changes in CVD risk factors over time may underestimate the association between NAFLD and outcomes defined by the study. In addition, we noted that Ahmed et al1 adjusted for the risk factors of CVD together. However, it seemed that not all included risk factors were associated with NAFLD-related CVD events. A recent meta-analysis5 has shown significant effects of type 2 diabetes and plasma LDL-cholesterol concentrations, rather than body mass index, smoking, or hypertension, on the association between NAFLD and the risk of CVD events. Therefore, an overall discussion of all included CVD risk factors may result in an exaggeration of certain factors. In conclusion, it is important to adjust for CVD risk factors, but whether adjusting for changes in CVD risk factors over time is appropriate and which CVD risk factors should be taken into account may need further discussion.
Identification of two tofacitinib subpopulations with different relative risk versus TNF inhibitors: an analysis of the open label, randomised controlled study ORAL Surveillance
Authors: Lars Erik Kristensen, Silvio Danese, Arne Yndestad, Cunshan Wang, Edward Nagy, Irene Modesto, Jose Rivas, Birgitta Benda
Journal: Annals of the Rheumatic Diseases (2023)

Based on primary results from ORAL Surveillance, an event-driven clinical trial of risk-enriched patients, identify subpopulations with different relative risk (ie, 'high-risk' and 'low-risk') with tofacitinib versus tumour necrosis factor inhibitors (TNFi).
Similar outcomes following non-first-degree and first-degree related donor haploidentical hematopoietic cell transplantation for acute leukemia patients in complete remission: a study from the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Authors: Yishan Ye, Myriam Labopin, Jia Chen, Zafer Gulbas, Xi Zhang, Yener Koc, Didier Blaise, Fabio Ciceri, Emmanuelle Polge, Mohamed Houhou, Lin Li, Yi Luo, Depei Wu, He Huang, Mohamad Mohty, Norbert-Claude Gorin
Journal: Journal of Hematology & Oncology (2023)

There are situations where non-first-degree (NFD) related donors have to be considered as alternatives to first-degree (FD) related donors for haploidentical hematopoietic cell transplantation (HAPLO). However, the efficacy of these NFD related transplants remains uncertain. All consecutive adult patients (≥ 18 years) with acute myelogenous leukemia (AML) or acute lymphocytic leukemia (ALL) in CR who underwent a first HAPLO between 2010 and 2021 in the European Society for Blood and Marrow Transplantation (EBMT) registry were analyzed. Exact matching and propensity score matching was used. The NFD-to-FD ratio was 1:3. 2703 patients (AML: n = 2047; ALL: n = 656) in CR received a first HAPLO from either NFD (n = 154) or FD (n = 2549) related donors in 177 EBMT centers. 123 NFD and 324 FD HAPLO were included for analysis after matching. Median patient age was 35.6 and 37.2 for the NFD and FD cohorts, respectively. Both cohorts reached good engraftment rates (NFD: 95.7% vs. FD, 95.6%; p = 0.78). The 2-year relapse incidence (NFD, 21.1% vs. FD, 22.6%; p = 0.84) and non-relapse mortality (NRM) (NFD, 13.2% vs. FD, 17.7%; p = 0.33) were not significantly different. The 2-year overall survival (OS) (NFD, 71.8% vs. FD, 68.3%; p = 0.56), leukemia-free survival (LFS) (NFD, 65.7% vs. FD, 59.7%; p = 0.6) and graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) (NFD, 50.9% vs. FD, 47.8%; p = 0.69) also showed no significant differences. The two cohorts showed no difference in terms of cumulative day 180 grade II-IV, grade III-IV acute GVHD, 2-year cumulative incidences of chronic and extensive chronic GVHD. For HAPLO in patients with acute leukemia, NFD related donors could be equivalent substitutions when FD related donors are not available.
Sterol regulatory element-binding protein 2 maintains glioblastoma stem cells by keeping the balance between cholesterol biosynthesis and uptake
Authors: Danling Gu, Fengqi Zhou, Hao You, Jiancheng Gao, Tao Kang, Deobrat Dixit, Qiulian Wu, Kailin Yang, Shusheng Ci, Danyang Shan, Xiao Fan, Wei Yuan, Qian Zhang, Chenfei Lu, Daqi Li, Ningwei Zhao, Zhumei Shi, Wei Gao, Fan Lin, Jianghong Man, Qianghu Wang, Xu Qian, Stephen C Mack, Weiwei Tao, Sameer Agnihotri, Nu Zhang, Yongping You, Jeremy N Rich, Junxia Zhang, Xiuxing Wang
Journal: Neuro-Oncology (2023)

Abstract Background Glioblastomas (GBMs) display striking dysregulation of metabolism to promote tumor growth. Glioblastoma stem cells (GSCs) adapt to regions of heterogeneous nutrient availability, yet display dependency on de novo cholesterol biosynthesis. The transcription factor Sterol Regulatory Element-Binding Protein 2 (SREBP2) regulates cholesterol biosynthesis enzymes and uptake receptors. Here, we investigate adaptive behavior of GSCs under different cholesterol supplies. Methods In silico analysis of patient tumors demonstrated enrichment of cholesterol synthesis associated with decreased angiogenesis. Comparative gene expression of cholesterol biosynthesis enzymes in paired GBM specimens and GSCs were performed. In vitro and in vivo loss-of-function genetic and pharmacologic assays were conducted to evaluate the effect of SREBP2 on GBM cholesterol biosynthesis, proliferation, and self-renewal. Chromatin immunoprecipitation quantitative real-time PCR was leveraged to map the regulation of SREBP2 to cholesterol biosynthesis enzymes and uptake receptors in GSCs. Results Cholesterol biosynthetic enzymes were expressed at higher levels in GBM tumor cores than in invasive margins. SREBP2 promoted cholesterol biosynthesis in GSCs, especially under starvation, as well as proliferation, self-renewal, and tumor growth. SREBP2 governed the balance between cholesterol biosynthesis and uptake in different nutrient conditions. Conclusions SREBP2 displays context-specific regulation of cholesterol biology based on its availability in the microenvironment with induction of cholesterol biosynthesis in the tumor core and uptake in the margin, informing a novel treatment strategy for GBM.